AbstractMultiple sclerosis (MS) is associated with genetic susceptibility and unknown environmental triggers, possible viral infections, but the specific etiological mechanism that subsequently develops into an inflammatory/autoimmune cascade of events is poorly understood. Recently, genetic variants of 2′,5′‐ oligoadenylate synthetase 1 (OAS1) gene, a critical enzyme involved in innate antivirus response, have been associated with differential enzyme activity and type 1 diabetes in both case–control and family studies. We hypothesized that polymorphisms in the OAS1 gene could influence the susceptibility to MS. To test this hypothesis, we conducted a case–control study of 333 patients with MS and 424 healthy controls and genotyped two OAS1 single nucleotide polymorphisms (SNPs) by restriction fragment length polymorphism method: rs 10774671, A/G SNP altering the splicing site at the seventh exon, and rs 3741981, a nonsynonymous (Ser162Gly) A/G SNP in the third exon. Haplotype but not single‐marker analysis revealed an association of the haplotype created by the G allele at rs 10774671 and the A allele at rs 3741981 with the susceptibility to MS (P value = 8.8 × 10−5). Subjects carrying this haplotype had an increased risk of MS comparing with those not carrying it (odds ratio = 4.7, 95% confidence interval 2.1–10.9). Our findings indicate that the OAS1 gene polymorphisms may confer susceptibility to MS or serve as markers of functional variants and suggest that OAS1 activity is involved in the etiology of the disease. Future studies in a larger sample and association analysis with functional variants will clarify the role of the OAS1 gene in the susceptibility to MS.